Abstract

Background Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive
cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail
to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response.

Objective To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the
progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC)
in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response
to engage and target tumour epithelial cells.

Methods A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal
features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and
the biological outcomes determined.

Results PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known
to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells.
Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated
CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma.

Conclusions Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation.
Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected
latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease.